Molecular Characterization of 103 Ovarian Serous and Mucinous Tumors

Abstract

The pathogenesis of ovarian carcinomas is heterogeneous, with even the same entities showing great variance. In our study we investigated the mutations of the BRAF, KRAS, and p53 genes in serous and mucinous borderline tumors and in low grade and high grade serous and mucinous tumors. The mutations of BRAF and KRAS genes have been shown in 60% of borderline and low grade (well differentiated) serous and mucinous tumors, but very rarely in high grade (moderately and poorly differentiated) carcinomas. However mutations of p53 are very common in high grade tumors and this indicates a "dualistic" model of ovarian tumorigenesis. A total of 80 serous tumors, including serous borderline, low grade and high grade tumors, and 23 mucinous tumors, including borderline and invasive tumors were analysed for BRAF and KRAS mutations using real time PCR method followed by melting point analysis. P53 mutation was investigated by immunohistochemistry. We assumed mutation of the p53 gene when 100% of tumor cells showed strong nuclear positivity. We observed differences in genetic alterations in the development of the low grade tumors and between low and high grade tumors too. In some bilateral or stage II-III cases we observed differences between the mutation status of the left and right ovarian tumors and between the primary tumor and its implants. In one case in a tumor with micropapillary pattern showing high grade nuclear atypia we could detect mutations in both KRAS and p53 genes. The majority of our mucinous ovarian tumor cases showed a KRAS mutation. We have not found mutations of the BRAF and p53 genes in these cases. We have found as have others, that there is a dualistic pathway of ovarian carcinogenesis. In the majority of cases, low grade epithelial tumors develop in a stepwise manner due to genetic alterations of the members of MAP-kinase pathway; however mutation of the p53 gene is the key event in the development of high grade tumors.

Ovarian Cancer, Version 1.2016, NCCN Clinical Practice Guidelines in Oncology

“…51 Recent molecular characterization of clear cell, mucinous, or grade 1 (low-grade) tumors suggests that mutations in these histologies are different from those in highergrade tumors. [83][84][85] Ovarian cancer can be divided into types 1 and 2 based on these molecular alterations. Data suggest that serous tumors can be categorized as either low grade (most grade 1 serous tumors) or high grade (most grade 2 or 3 serous tumors).…”

Potential signaling pathways as therapeutic targets for overcoming chemoresistance in mucinous ovarian cancer (Review)

“…Genetic alterations of the RAS/RAF/MAPK, PI3K/Akt and WNT/β-catenin signaling pathway members have been reported to increase in a stepwise manner from mucinous borderline tumors to mucinous ovarian cancer (18). The crosstalk between the growth factor and WNT signaling pathways may sustain PI3K/GSK3β/β-catenin signal activation, which is associated with chemoresistance in cancer (18).…”

Monoclonal Origin of Peritoneal Implants and Lymph Node Deposits in Serous Borderline Ovarian Tumors (s-BOT) With High Intratumoral Homogeneity

“…Low-grade serous ovarian carcinomas and s-BOT as their putative precursor lesions are genetically relatively stable and typically display KRAS and BRAF mutations as early events within its carcinogenesis (5,7,8,12,18,19). Up to one third of patients with s-BOT represent prognostically relevant peritoneal implants and/or pelvic/para-aortal lymph node involvement (10).…”

“…Two major hypotheses have been proposed (3,15,19). One favors the monoclonal origin, arguing that the extraovarian lesions derive from neoplastic cells that are shed from the primary ovarian tumor with consecutive peritoneal implantation or their transportation by small lymphovascular channels to pelvic/para-aortal nodes.…”